Fluorine Bonding Enhances the Energetics of Protein-Lipid Binding in the Gas Phase

Lan Liu, Nobar Jalili, Alyson Baergen, Simon Ng, Justin Bailey, Ratmir Derda, John S. Klassen

This paper reports on the first experimental study of the energies of noncovalent fluorine bonding in a protein-ligand complex in the absence of solvent. Arrhenius parameters were measured for the dissociation of gaseous deprotonated ions of complexes of bovine β-lactoglobulin (Lg), a model lipid-binding protein, and four fluorinated analogs of stearic acid (SA), which contained (X =) 13, 15, 17, or 21 fluorine atoms. In all cases, the activation energies (Ea) measured for the loss of neutral XF-SA from the (Lg + XF-SA)(7–) ions are larger than for SA. From the kinetic data, the average contribution of each > CF2 group to Ea was found to be ~1.1 kcal mol(–1), which is larger than the ~0.8 kcal mol(–1) value reported for > CH2 groups. Based on these results, it is proposed that fluorocarbon–protein interactions are inherently stronger (enthalpically) than the corresponding hydrocarbon interactions.